Assembly of Complex 1,4-Cycloheptadienes by (4+3) Cycloaddition of Rhodium(II) and Gold(I) Non-Acceptor Carbenes

Article abstract of DOI:10.1002/anie.202012092

The formal (4+3) cycloaddition of 1,3-dienes with Rh(II) and Au(I) non-acceptor vinyl carbenes, generated from vinylcycloheptatrienes or alkoxyenynes, respectively, leads to 1,4-cycloheptadienes featuring complex and diverse substitution patterns, including natural dyctiopterene C′ and a hydroxylated derivative of carota-1,4-diene. A complete mechanistic picture is presented, in which Au(I) and Rh(II) non-acceptor vinyl carbenes were shown to undergo a vinylcyclopropanation/Cope rearrangement or a direct (4+3) cycloaddition that takes place in a non-concerted manner.

Full text of DOI:10.1002/anie.202012092

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Assembly of Complex 1,4-Cycloheptadienes by (4+3)
Cycloaddition of Rhodium(II) and Gold(I) Non-Acceptor Carbenes
Authors: Antonio M. Echavarren, Helena Armengol-Relats, and Mauro
Mato
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012092
Link to VoR: https://doi.org/10.1002/anie.202012092

10.1002/anie.202012092
Angewandte Chemie International Edition
Assembly of Complex 1,4-Cycloheptadienes by (4+3) Cycloaddition
of Rhodium(II) and Gold(I) Non-Acceptor Carbenes
Helena Armengol-Relats,† Mauro Mato,† and Antonio M. Echavarren*
Here, we report the reactivity of these catalytically-generated
intermediates with 1,3-dienes to give a diverse range of 1,4-
cycloheptadienes through a (4+3) formal cycloaddition process.
We also present a complete mechanistic picture in which two main
pathways for the cycloaddition process were studied both
experimentally and theoretically. Our theoretical and experimental
study shows that, depending on the substitution pattern of the
substrates, a direct closing of a cationic intermediate is sometimes
favored rather than the well-stablished cyclopropanation–Cope
rearrangement pathway.
Abstract: The formal (4+3) cycloaddition of 1,3-dienes with Rh(II) and
Au(I) non-acceptor vinyl carbenes, generated from
vinylcycloheptatrienes or alkoxyenynes, respectively, leads to 1,4-
cycloheptadienes featuring complex and diverse substitution patterns,
including natural dyctiopterene C’ and a hydroxylated derivative of
carota-1,4-diene. A complete mechanistic picture is presented, in
which Au(I) and Rh(II) non-acceptor vinyl carbenes were shown to
undergo a vinylcyclopropanation/Cope rearrangement or a direct
(4+3) cycloaddition that takes place in a non-concerted manner.
Introduction
7-Membered carbocycles are important motifs present in a
variety of natural products (Scheme 1, A).[1] However, they can be
challenging to synthesize through traditional cyclization
pathways.[1,2] The synthesis of these medium-sized rings often
relies on the use of cycloaddition strategies,[3] ring expansions,[4]
5
]
6 ]
ring-closing metathesis,[
or cross-coupling reactions.[
In
particular, the divinylcyclopropane–cycloheptadiene Cope
rearrangement has been established as a versatile alternative for
the construction of 1,4-cycloheptadienes.[7] The main challenge of
this approach is the stereoselective assembly of the key cis-
divinylcyclopropane with the appropriate substitution pattern. In
this regard, Davies and co-workers pioneered the reaction of 1,3-
dienes with donor–acceptor vinyl carbenes, generated from diazo
compounds, to give cycloheptadienes after cyclopropanation and
Cope rearrangement, through an overall formal (4+3) cycloaddition
process (Scheme 1, B).[8] This strategy was successfully applied
by several groups for the synthesis of 7-membered carbocycles,[9]
but it displays the inherent problems associated to diazo
compounds,[10] limiting the methodologies to the use of acceptor
metal carbenes.[11] Different gold(I)-catalyzed (4+3) cycloadditions
were developed over the years, mainly based on the reaction of
1,3-dienes with allenes[ 12 ] or vinyl carbenes generated from
propargyl esters,[13] cyclopropenes[14] or by recombination of linear
dienediynes.[ 15 ] In our pursuit to identify new sources of non-
acceptor metal carbenes, we have established both 7-vinyl-1,3,5-
cycloheptatrienes (1) and 5-alkoxy-1,6-enynes (6) as suitable
precursors. The former can undergo metal-catalyzed retro-
Buchner reactions (releasing aromatic units),[16] and the latter can
Scheme 1. A. Examples of bioactive natural products containing 7-membered
carbocycles. B. Classical approach for the assembly of 1,4-cycloheptadienes by
diazo-carbene chemistry. C. This work: formal (4+3) cycloaddition of dienes with
non-acceptor vinyl carbenes generated from cycloheptatrienes or alkoxyenynes.
Results and Discussion
We found that the reaction of 1a with 1,3-cyclohexadiene in the
presence of Rh2TFA4 at 40 ºC gives cleanly the product of (4+3)
cycloaddition 3a in excellent yield, as a single diastereoisomer
(Table 1, entry 1). Notably, with this system, no traces of
dinvinylcyclopropane 3a’ were observed after 18 h. The same
reaction can be carried out using gold(I) catalyst A with bulky
JohnPhos ligand although with lower yield (Table 1, entry 5). In
contrast, other Lewis acids, or even less electrophilic Rh(II)
complexes, failed to give significant amounts of product 3a (Table
1, entries 6-8). Furthermore, the reaction could be carried out in a
significantly wide range of temperatures, or without protective inert
atmosphere, showing only a moderate drop in yield (Table 1,
entries 2-4).
take part in
a gold(I)-catalyzed cycloisomerization/migration
cascade sequence[ 17 ] generating non-acceptor vinyl carbene
intermediates with diverse substitution patterns (Scheme 1, C).
[] H. Armengol-Relats, M. Mato, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute
of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
Departament de Química Analítica i Química Orgànica, Universitat
Rovira i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
† These authors contributed equally to this work.
Table 1. Optimization and control experiments.[a]
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012092
Angewandte Chemie International Edition
Ph
(5) (Scheme 3, B), a natural pheromone isolated from brown
algae.[22]
Rh2TFA4 (5 mol%)
+
1,2-DCE, 40 ºC, 18 h
- mesitylene
Ph
R
1a
Entry
2b (4 equiv)
3a
Yield 3a
Rn
Rh2TFA4 (5 mol%)
Rn
+
Deviations from Standard Conditions
none
R
1,2-DCE, 40 ºC, 12–20 h
1
2 (4 equiv)
3
1
2
3
4
5
6
7
8
91%
75%
82%
65%
70%
8%
3a Ar = Ph (91%) (82% 1 mmol) [∆G‡ = 21.5][a]
3b Ar = 4-(CO2Fc)C6H4 (72%)
3c Ar = 3,5-(CF3)2C6H3 (67%)
3d Ar = 4-(MeO)C6H4 (82%)
Ar
under air and non-dry solvent
25 ºC instead of 40 ºC
3e Ar = 3,5-Cl2C6H3 (70%)
3f Ar = 2-IC6H4 (61%)
3b
80 ºC instead of 40 ºC
3g Ar = 2-Br-4,5-(OCH2O)C6H2 (60%)
[Au] instead of Rh2TFA4
MeO
TMSO
OMe
Ar
Ph
3j Ar = C6H5 (83%)
3k Ar = 4-(CO2Fc)C6H4 (65%)
ZnBr2 (20 mol%) instead of Rh2TFA4
InCl3 (20 mol%) instead of Rh2TFA4
Rh2(esp)4 instead of Rh2TFA4
3h (60%)
3i (36%)
3l Ar = C6H5 (53%)
3m Ar = 3-BrC6H4 (43%)
3n Ar = 2-(
Ph
n/d
)C H4 (57%)
TMS
6
7%
Ar
K2CO3
95%[c]
3p (87%)
(7:1 rr)
3o Ar = 2-(
)C H
6
H
4
[a] Standard conditions: Reaction of 1a with 2b (4 equiv), in the presence of
Rh2TFA4 (5 mol%), in dry 1,2-dichloroethane (0.15 M), under Ar, at 40 ºC, 18 h.
[Au] = A = [(JohnPhos)Au(MeCN)]SbF6; n/d = not detected.
Ph
Ph
Ph
Ph
Ph
3s (60%)
[∆G‡ = 19.5][a]
Ph
A range of styryl cycloheptatrienes 1 were successfully employed,
showing the tolerance to both electron-rich and electron-poor
aromatic rings on the carbene fragment (3a-g) (Scheme 2).
Different aryl halides (3e-g, 3m) and a dienyl carbene (3h) could
be transferred, and even a TMS-alkyne was tolerated (3n), which
3t (79%)[b]
3u (52%)
3r (91%)
[∆G‡ = 21.8][a]
3q (70%)
[∆G‡ = 19.9][a]
[∆G‡ = 16.1][a]
Ph
3w’ (66%)
[∆G‡ = 29.0][a]
3v (50%)
could be easily deprotected afterwards (3o).
A
double
Ar
decarbenation/(4+3) cycloaddition was also carried out giving
directly 3v in 50% yield as a single diastereoisomer, forging six new
stereocenters in one step. The relative configuration of the bicyclic
products was inequivocally confirmed by x-ray analysis of 3v and
ferrocene-derivative 3b.[18] Then we explored the scope of 1,3-
dienes. Non-cyclic dienes could also be used (3q), including
different 1-oxo-1,3-dienes which led to products 3i-k.[ 19 ] The
reaction of 1a with α-terpinene afforded 3p in high yield and 7:1
160 ºC, 24 h
xylenes
Ar
3x’ Ar = Ph (53%) [∆G‡ = 30.9][a]
3y’ Ar = 4-(CO2Fc)C6H4 (50%)
3x (99%)
3y (40%)
Scheme 2. Reaction scope of the decarbenation/(4+3) cycloaddition sequence.
[a] Activation energy (kcal/mol at 25 ºC) calculated for the free Cope
rearrangement of the corresponding dinvinylcyclopropanes 3’. [b] At 60 ºC for 20
h. [c] K2CO3 (2 equiv) in MeOH/DCM at 25 ºC, 3 h. Fc = ferrocenyl.
ratio of regioisomers, corresponding to
a more favorable
cyclopropanation of the less-hindered double bond, followed by a
diastereospecific Cope rearrangement. Cyclic dienes of several
sizes (5-7) were successfully employed in the (4+3) cycloaddition
(3l-u). On the other hand, we observed that the reaction of 1a with
1,3-cyclooctadiene at 40 ºC afforded only cyclopropane 3x’. A
OMe
A.
3m[a]
3o[b]
Ar
OMe
3m Ar = 3-BrC6H4
3z (74%)
similar
result
was
obtained
when
using
1,1,4,4-
3o Ar = 2-(
)C H
H
6 4
N
3aa (71%)
O
tetramethylbutadiene (3w’). The barrier of the free Cope
rearrangement was calculated for several substrates leading to a
simple predictive model: products of (4+3) cycloaddition were
observed when the calculated barriers were lower that 22 kcal/mol
(Scheme 2, ∆G‡ in blue boxes), whereas cyclopropanes were
isolated for higher barriers (red boxes).[20] Thus, barriers of 29.0
and 30.9 kcal/mol were calculated for 3w’ and 3x’, respectively.
The mechanistic hypothesis was confirmed by obtaining 1,4-
cycloheptadienes 3x and 3y[18] by heating 3x’ and 3y’ up to 160 ºC
for 24 h.
H2
Pd/C [c]
Ph
4 (82%)
saturated bioisosteres
of benzene
Ph
3a
B.
Rh2TFA4
(5 mol%)
+
1,2-DCE, 40 ºC
5 (48%)
nBu
24 h
(±)-dictyopterene C'
(algae pheromone)
1b
2c
Scheme 3. A. Diversification and reactivity of cycloheptadienes 3. [a] 3,5-
Dimethoxyphenyl boronic acid, Cs2CO3, PdCl2/RuPhos (cat), dioxane/water (5:1),
80 ºC, 2 h. [b] 4-Iodo-3,5-dimethylisoxazole, Pd(PPh3)2Cl2 (cat), CuI (cat),
triethylamine, 50 ºC, 20 h. [c] H2 (1 atm, balloon), Pd/C (cat), ethanol, 25 ºC, 18
h. B. Total synthesis of (±)-dictyopterene C’.
Other cycloheptadienes 3z and 3aa were easily obtained from 3m
and 3o, respectively, by cross-coupling reactions (Scheme 3, A). It
was possible to fully hydrogenate 3a under mild conditions,
obtaining 2-phenylbicyclo[3.2.2]nonane (4), which resembles an
alternative saturated benzene bioisostere.[ 21 ] Furthermore, to
illustrate the potential of the methodology, starting from 1b and 1,3-
butadiene, we prepared in a single reaction flask dictyopterene C’
Vinylcarbenes arising from the gold(I)-catalyzed isomerization 5-
alkoxy-1,6-enynes 6 also undergo a similar (4+3) cycloadditions
(Table 2). Hydroazulenes 7 were obtained in one step, in a
This article is protected by copyright. All rights reserved.

10.1002/anie.202012092
Angewandte Chemie International Edition
stereoselective manner, bearing the common core of the daucene
family of natural products.[ 23 , 24 ] We found that the selectivity
between the formation of cycloheptadiene 7 or cyclopropane 8 is
dependant on the sterics and electronics of the catalyst.[25] Catalyst
A provided the highest selectivity towards the formation of
cyclopropane 8a (Table 2, entry 1: 1:2 7a/8a), while bulkier B gave
a 1:1 ratio of 7a/8a (Table 2, entry 2). A less donating phosphite
ligand in catalyst D led to selective formation of cycloheptadiene
7a (Table 2, entry 4: 15:1 7a/8a). The same effect can also be
observed in the different ratio of products obtained with catalysts E
and F, where more -donating triethylphosphine favored
cyclopropanation product 8a in contrast with triphenylphosphine
(Table 2, entries 5 and 6). Longer reaction times translated into
lower yields, indicating decomposition, while the ratio of products
was maintained (Table 2, compare entries 1 and 7). Finally, in the
presence of Rh2TFA4 only unreacted 1,6-enyne 6a was recovered
(Table 2, entry 8).
methyl substituent at the 2-position (isoprene) led to a drop in
selectivity, still giving 7f as the main product with both catalysts.
Exchanging the methyl by a phenyl (8g), or adding a second methyl
group (8i) inverted the selectivity, giving cylopropanes as major
products. The reaction with an electronically biased 2-oxy-1,3-
diene delivered 7h and 9 as a 10:1 mixture using catalyst A.
Catalyst D afforded only (4+3) product 7h and bulkier complex B
led to a 1:1.4 ratio of 7h and 9, which is the product of formal (3+2)
cycloaddition. Replacing the PNP migrating group by an acetate in
the 1,6-enyne led to a drop of yield, but mantaining the same
tendency in selectivity observed before, obtaining only 7h’.[ 27 ]
Finally, antracene was found to be a good reaction partner for the
(4+3) cycloaddition, giving 7j in 68% yield as a single isomer. The
PNP group in compound 7f was removed, delivering 7fa as a
crystalline solid in 34% yield over two steps. This allowed the
confirmation of the relative configuration of the (4+3) product by x-
ray diffraction.[18] Compound 7fa is a hydroxylated analogue of
carota-1,4-diene (7fb), a natural product isolated from Rosa
rugosa leaves.[28]
Table 2. Catalyst screening for the gold(I)-catalyzed reaction of 1,6-enyne 6a with
cyclopentadiene (2a).[a]
OR
R1
OPNP
R1
[Au] (1 mol%)
R1
[Au] (1 mol%)
+
+
+
+
CH2Cl2, 23 ºC, 2 h
CH2Cl2, 23 ºC, 2 h
OR
OR
OPNP
OPNP
7a
6
2 (3 equiv)
7
8
2a (3 equiv)
6a
8a
Entry
[Au]
A
Conversion
100%
Yield 7a
Yield 8a
51% (12:1)
36%
1[b]
2
26% (7:1)
OPNP
7a + 8a
A: 26% (7:1 dr) +
51% (12:1 dr)
D: 60% (5:1) + 4%
OPNP
OPNP
OPNP
B
100%
40% (5.7:1)
36% (17:1)
60% (5:1)
40% (4.7:1)
27% (4.4:1)
18% (8:1)
-
7b
7c
8d
A: 81% (6.4:1 dr)
D: 93% (1.5:1 dr)
A: 68% (9:1 dr)
A: 83% (3:1 dr)
3
C
100%
12%
OTIPS
4
D
100%
4%
Ph
5[c]
6[c]
7[d]
8[d,e]
E
100%
19%
OR
7h’ (R = Ac)
D: 45%
OPNP
OPNP
OPNP
F
91%
31%
7e + 8e
A: 42% + 9%
D: 28% + 24%
7f + 8f
A: 36% + 30%
D: 42% + 32%
7g + 8g
A: 31% + 38%
7h (R = PNP)
A: 68% + 7% 9
B: 39% + 54% (37%)[a]
D: 72%
A
100%
30%
9
OPNP
H
[Rh] (5 mol%)
0%
-
9
iPr
tBu
iPr
tBu
N
N
D: [(ArO)3PAu(PhCN)]SbF6
Ar=2,4-di(tert-butyl)phenyl
OPNP
PNPO
P
Au NCMe
OTIPS
R
7i + 8i
D: 32% + 50% (7.2:1 dr)
iPr
7j
A: 67%
iPr
Au
SbF6
E: Ph3PAuCl
F: Et3PAuCl
N
SbF6
R
R
1. Cu(acac)2, NaBH4
2. CAN (30% 2 steps)
Ph
A: R=H
B: R=iPr
C
7fb
carota-1,4-diene
[a] Standard conditions: Reaction of 6a with 2a (3 equiv), in the presence of [Au]
catalyst (1 mol%), in CH2Cl2 (0.2 M), at 23 ºC, 2 h; NMR yields using
tricholoroethene as internal standard, d.r. in parenthesis. [b] Isolated yields (as a
mixture of 7a and 8a). [c] Addition of 1 mol % of NaBArF4. [d] 24 h reaction time.
[e] Reaction performed at 40 ºC. PNP = p-nitrophenyl, [Rh] = Rh2TFA4.
OPNP
7f
7fa
Scheme 4. Reaction scope of the cycloisomerization/OR-migration/(4+3)
cycloaddition. Yields of both 7 and 8 are indicated for each substrate, unless only
one of the two products (depicted) was obtained. [a] In parenthesis, isolated yield
of 9 after treatment with HCl (cat.) in EtOH for 24 h and purification.
We investigated the reaction scope using complexes A and D
(Scheme 4). Tetramethyl and pentamethyl cyclopentadiene
afforded exlusively (4+3)-cycloaddition products 7b and 7c,
respectively, with both catalysts. Interestingly, while the yield was
slightly higher with phosphite complex D, JohnPhos catalyst A
gave higher diastereoselectivity. In contrast, 1,3-cyclohexadiene
only afforded cyclopropane product 8d.[ 26 ] Acyclic dienes also
reacted in moderate to good yields. For 1,3-butadiene, gold(I)
complex A was more selective for the formation 7e than catalyst D,
that essentially gave a 1:1 mixture of 7e and 8e. Introducing a
We studied the mechanism of the two systems by DFT calculations
at 6-311G++(d,p)(H, C, N, O, F, P) + LANL2TZ(Au, Rh) // B3LYP-
D3/6-31G(d,p)(H, C, N, O, F, P) + LANL2DZ(Au, Rh) level of theory,
taking into account the solvent effect (SMD = 1,2-dichloroethane
or dichloromethane). For the first class of substrates, the process
starts by the rhodium(II)-catalyzed retro-Buchner reaction of
cycloheptatriene 1a (decarbenation) to give styryl carbene III
releasing mesitylene (Scheme 5, A).[29] An activation barrier of 18.0
kcal/mol was calculated from I, which was identified as local
This article is protected by copyright. All rights reserved.

10.1002/anie.202012092
Angewandte Chemie International Edition
minimum. After exchanging mesitylene for 1,3-cyclohexadiene (IV),
pathway, we removed the Rh(II) catalyst after 1.5 h of reaction, and
then followed the evolution of the resulting mixture (Scheme 5, C).
the most favorable pathway corresponds to
a stepwise
cyclopropanation, in which the formation of cis open intermediate
Va is kinetically more favored than the trans by 2.6 kcal/mol, which
would account for a perfect cis selectivity (80:1).[30] The resulting
open intermediate Va can evolve through two pathways: an almost
barrierless cyclopropanation (TSVa-VI) giving Rh(II)-coordinated cis-
divinylcyclopropane VI or a direct (4+3) closing (TSVa-VII), which
affords Rh(II)-coordinated final product 3a (VII). Although both
pathways are energetically feasible, the cyclopropanation TS is
lower in energy (∆∆G‡ = 2.1 kcal/mol). The resulting cyclopropane
can further evolve through Cope rearrangement. Rh(II)-
coordinated divinylcyclopropane VI is in downhill equilibrium with
This showed a clean thermal conversion of intermediate
divinylcyclopropane 3a’ into 1,4-cycloheptadiene 3a during 12 h at
30 ºC. The successful removal of the Rh(II) catalyst was confirmed
by the recovery of the remaining cycloheptatriene 1a. All in all, the
entire mechanistic analysis is in agreement with the experimental
observations, and explains why these vinyl Rh(II) carbenes
generated from cycloheptatrienes lead cleanly to (4+3)
cycloaddition products.
A
different scenario was found for the Au(I)-catalyzed
transformation of enyne 6a (Scheme 6). The first steps consist in
an enyne cycloisomerization cascade involving a 5-exo-dig
cyclization, followed by a 1,5-migration of the OR group to form
vinyl carbene IX (Scheme 6, A).[31] This sequence contains the
Turnover Limiting Step, with a overall energy barrier of 6.1 kcal/mol
from local minimum VIII. Next, the intermolecular trapping of
intermediate IX by cyclopentadiene (2a) proceeds stepwise
(Scheme 6, B).[32] The two possible orientations of cyclopentadiene
approaching carbene IX afford diastereomeric allyl carbocations
Xa and Xb through TSIX-Xa and TSIX-Xb, respectively. These two TS
differ in 2.6 kcal/mol, which is consistent with the high
diastereomeric ratio found experimentally in the final products.
free divinylcyclopropane 3a’
+
I
(1,3-cyclohexadiene η2-
coordinated to Rh2TFA4). This results in an activation barrier of
20.3 kcal/mol (larger, but rather similar than that for the retro-
Buchner step) for the Rh(II)-coordinated Cope rearrangement
(TSVI-VII), which makes it the turnover-limiting step of the entire
process. The calculated energies are in agreement with the overall
kinetic profile of the reaction (Scheme 5, B): following the reaction
by 1H NMR, we observed an accumulation of intermediate
cyclopropane 3a’. Alternatively, after decoordination from Rh(II),
free cyclopropane 3a’ can undergo a thermal Cope rearrangement
(TS3a’-3a), with an only slightly higher energy barrier (∆∆G‡ = 1.2
kcal/mol). In order to prove the existance of the catalyst-free
Decabenation (Ref 29)
Cyclopropanation / Direct (4 + 3)
Cope Rearrangement
A.
Free Cope Rearrangement at 30 °C
[Removal of Rh Catalyst after 1:30 h]
∆∆G‡ = 2.6
cis favored
C.
TSI-II
Ph
100%
80%
60%
40%
20%
0%
18.0
Ph
Ph
[Rh]
Divincylyccylcolohperpotpaadnieen3ae' 3a
[Rh]
∆∆G‡ = 2.1
cyclopropanation
favored vs
divinylcyclopropane 3a’
Remaining Cycloheptatriene 1a
[Rh]
remaining 1a
Cycloheptadiene 3a
time (h)
direct (4+3)
Ph
[Rh]
Ph
TStrans
TScis
0,0
2,0
Ph
4,0
6,0
8,0 10,0 12,0 14,0
7.7
5.1
IV-Vb
[Rh]
IV-Va
Ph
Free Cope ∆G‡ = 21.5
[Rh]-Cope ∆G‡ = 20.3
∆∆G‡ = 1.2
II
I +
I
2b
[Rh]
III
1.7
IV
0.0
2b
-0.1
-1.1
-2.3
Ph
1a
-0.8
TS3a’-3a
simplified
mechanism
from Ref 29
TSVa-VII
mesitylene
TSVI-VII
[Rh]
IV
[Rh]
-3.3
Ph
-4.4
[Rh]
Va
[Rh] = Rh2(TFA)4
TSVa-VI
-5.7
TSVI-VII
Ph
Ph
100%
Overall Reaction Profile at 50 °C
B.
80%
60%
40%
20%
0%
[Rh]
[Rh]
Cycloheptatriene 1a
VI
cycloheptadiene 3a
divinylcyclopropane 3a’
Divinylcyclopropane 3a'
-18.6
cycloheptatriene 1a
[Rh]
VI
Cycloheptadiene 3a
Ph
3a
time (h)
VII
I + 3a’
2b
Ph
0,0
1,0
2,0
3,0
4,0
-22.6
-28.4
2b
I
[Rh]
3a
-30.6
Scheme 5. Overall mechanistic proposal for the decarbenation/(4+3) sequence based on both theoretical and kinetic observations. A. Free-energy profile for the Rh(II)-
catalyzed (4+3) formal cycloaddition by decarbenation of 1a and reaction with 2a (kcal/mol at 25 ºC). B. Overall kinetic profile of the reaction in TCE-d2 at 50 ºC, followed
by 1H NMR showing accumulation of intermediate 3a’. C. Kinetic profile of the free Cope rearrangement (after removing the Rh(II) catalyst) of 3a’ to give 3a in CDCl3 at
30 ºC followed by 1H NMR.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012092
Angewandte Chemie International Edition
8a would have to overcome 30.1 kcal/mol to rearrange into 7a,
while 8a’ can only be converted into 7a’ (and not 7a’’, which has
LAu+
A. Enyne isomerization mechanism (Ref 31):
AuL
RO
LAu
5-exo-dig
OR-migration
the relative configuration observed experimentally) by
a
RO
H
stereospecific Cope rearrangement, also with a high-energy barrier
of 34.3 kcal/mol. These results indicate that, in contrast to that
observed with products 3 (Scheme 2), densely substituted (4+3)
cycloaddition products 7, formed in the Au(I)-catalyzed stepwise
process, cannot be obtained by metal-catalyzed nor thermal Cope
rearrangement of the corresponding divinylcyclopropanes.
OR
Enyne Isomerization
Stepwise Cyclopropanation and (4+3) Cycloaddition
H
B.
6.1
AuL
H
H
OR
OR
LAu+
LAu+
0.0
0.0
TSXa-XIIa
TSXa-XIa
H
TSIX-Xa
-1.8
VIII
OR
-2.9
1
Conclusion
Xa
-5.0
-6.7
Xb
m
d
3
-3.6
s
e
TSXb-XIIb
TSXb-XIb
i
f
i
LAu+
e
f
n
i
-5.5
l
a
R
-4.1
p
To sum up, we have developed two new approaches for the
h
TSIX-Xb
-7.3
-7.6
XIb
XIa
c
m
m
∆∆G‡ = 0.5
(2+1) favored
vs (4+3)
i
-7.9
IX
e
o
s
r
synthesis of
a wide variety of structuraly complex 1,4-
m
f
H
H
OR
AuL
cycloheptadienes. Both reactions rely on the formal (4+3)
cycloaddition of non-acceptor vinyl metal carbenes with 1,3-dienes.
The first approach involves the rhodium(II)-catalyzed
H
LAu+
OR
8a’
-17.8
H
OR
decarbenation
or
retro-Buchner
reaction
of
7-vinyl
C. Au-free Cope Rearrangement:
-18.3
H
H
8a
cycloheptatrienes, releasing a molecule of mesitylene. In the
second approach, these intermedates are generated from 5-
alkoxy-1,6-enynes by a gold(I)-catalyzed cyclization/migration
cascade. We showed the potential of these two complementary
methodologies in the rapid construction of molecular complexity,
and in the total synthesis of natural compounds, such as
dictyopterene C’. Furthermore, we present a complete mechanistic
picture for both reactions, backed up by experiments and
-21.8
∆G‡ = 34.3
7a’’
-24.8
LAu+
OR
XIIa
not
H
OR
-24.9
7a
8a’
7a’
7a’’
-26.7
OR
OR
H
XIIb
H
∆G‡ = 30.1
H
LAu+
OR
OR
8a
7a
OR
Scheme 6. A. Enyne isomerization mechanism. B. Free-energy profile for the
Au(I)-catalyzed cycloisomerization/OR-migration/(2+1) and (4+3) cycloaddition
cascade reaction of 6a with 2a (kcal/mol at 25 ºC). L = JohnPhos, R = p-
nitrophenyl. C. Calculated energy barriers for the Au-free Cope rearrangement of
8a’ and 8a (kcal/mol at 25 ºC).
computations.
We
found
that
both
a
classical
vinylcyclopropanation/Cope rearrangement sequence or a direct
formal (4+3) cycloaddition are feasible, and the preference for each
pathway depends on the substitution pattern of the substrates and
intermediates.
Intermediates Xa and Xb can then evolve to deliver (2+1) or (4+3)
cycloaddition products. Starting from most populated intermediate
Xb, the formation of the cyclopropane ring in XIb through TSXb-XIb
is favored by 0.5 kcal/mol over the 7-membered ring-closing
towards XIIb through TSXb-XIIb. This translates into a 2.5:1
calculated ratio of (2+1)/(4+3) cycloaddition products 8a and 7a
after decomplexation, in excellent agreement with the experimental
results for this same system using catalyst A (2:1 8a/7a ratio, Table
2). Although the gold(I)-catalyzed interconversion of 8a to 7a is
energetically feasible and thermodynamically favored according to
the calculated values (∆G‡ = 14.7 kcal/mol, ∆G° = -6.6 kcal/mol),
we did not observe such transformation to take place
experimentally.[33] Finally, we calculated the energy barriers of the
thermal Cope rearrangement (Scheme 6, B). Divinylcyclopropane
Acknowledgements
We thank the Ministerio de Ciencia e Innovación (PID2019-
104815GB-I00, FPI predoctoral fellowship to M.M. and FPU
predoctoral fellowship to H.A.-R.), Severo Ochoa Excellence
Accreditation 2020-2023 (CEX2019-000925-S), the European
Research Council (Advanced Grant No. 835080), the AGAUR
(2017 SGR 1257), and CERCA Program/Generalitat de Catalunya
for financial support. We thank Dr. Cristina García-Morales for
assistance with DFT calculations and useful discussions. We also
thank the ICIQ X-ray diffraction unit.
Keywords: metal carbenes · decarbenation reactions · enyne
cycloisomerizations · cycloadditions · cycloheptadienes
[1]
For a review, see: K. T. de Oliveira, B. M. Servilha, L. de C. Alves, A. L.
Desiderá, T. J. Brocksom. Studies in Natural Products Chemistry 2014,
42, 421–463.
[7]
[8]
S. Krüger, T. Gaich, Beilstein J. Org. Chem. 2014, 10, 163–193.
a) H. M. L. Davies, Tetrahedron 1993, 49, 5203–5223; b) H. M. L. Davies,
D. G. Stafford, B. D. Doan, J. H. Houser, J. Am. Chem. Soc. 1998, 120,
3326–3331.
[2]
[3]
J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734–736.
For reviews, see: a) M. Harmata, Chem. Commun. 2010, 46, 8886–8903.
b) H. Pellissier, Adv. Synth. Catal. 2011, 353, 189–218; c) K. E. O. Ylijoki,
J. M. Stryker, Chem. Rev. 2013, 113, 2244–2266.
[9]
a) H. M. L. Davies, B. D. Doan, J. Org. Chem. 1998, 63, 657–660; b) H.
Ito, S. Takeguchi, T. Kawagishi, K. Iguchi, Org. Lett. 2006, 8, 4883–4885;
c) B. D. Schwartz, J. R. Denton, Y. Lian, H. M. L. Davies, C. M. Williams,
J. Am. Chem. Soc. 2009, 131, 8329–8332; d) R. G. Vaswani, J. J. Day, J.
L. Wood, Org. Lett. 2009, 11, 4532–4535; e) Y. Lian, L. C. Miller, S. Born,
R. Sarpong, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132, 12422–12425;
f) H. Sommer, T. Weissbrod, I. Marek, ACS Catal. 2019, 9, 2400–2406.
[4]
[5]
For a review, see: E. J. Kantorowski, M. J. Kurth, Tetrahedron 2000, 56,
4317–4353.
a) M. W. B. Pfeiffer, A. J. Phillips, J. Am. Chem. Soc. 2005, 127, 5334–
5335; b) J. A. Enquist, Jr, B. M. Stoltz, Nature 2008, 453, 1228–1231; c)
T. Ohyoshi, S. Funakubo, Y. Miyazawa, K. Niida, I. Hayakawa, H. Kigoshi,
Angew. Chem. Int. Ed. 2012, 51, 4972–4975; Angew. Chem. 2012, 124,
5056–5059.
[10] J. R. Fulton, V. K. Aggarwal, J. de Vicente, Eur. J. Org. Chem. 2005, 1479–
1492.
[11] a) H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103, 2861–2904;
b) D. Zhu, L. Chen, H. Fan, Q. Yao, S. Zhu, Chem. Soc. Rev. 2020, 49,
908–950.
[6]
a) S. Iimura, L. E. Overman, R. Paulini, A. Zakarian, J. Am. Chem. Soc.
2006, 128, 13095–13101. b) P. Gao, S. P. Cook, Org. Lett. 2012, 14,
3340–13.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012092
Angewandte Chemie International Edition
[18] CCDC 2027380-2027383 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
[12] For cycloaddition reactions of allenes, see: a) P. Mauleón, R. M. Zeldin,
A. Z. González, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 6348–6349;
b) I. Alonso, B. Trillo, F. López, S. Montserrat, G. Ujaque, L. Castedo, A.
Lledós, J. L. Mascareñas, J. Am. Chem. Soc. 2009, 131, 13020–13030;
c) N. Krause, C. Winter, Chem. Rev. 2011, 111, 1994–2009; d) F. López,
J. L. Mascareñas, Chem. Soc. Rev. 2014, 43, 2904–2915.
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
[19] The cis configuration for 3i–k was assigned based on
Crystallographic
Data
Centre
via
a
simple
diastereospecific Cope rearrangement model, see Supporting Information.
[20] For more details, see Supporting Information.
[21] P. K. Mykhailiuk, Org. Biomol. Chem. 2019, 17, 2839–2849.
[22] a) D. G. Müller, L. Jaenicke, M. Donike, T. Akintobi, Science 1971, 171,
815–817; b) R. E. Moore, J. A. Pettus, J. Mistysyn, J. Org. Chem. 1973,
39, 2201–2207; c) D. Grandjean, P. Pale, J. Chuche, Tetrahedron 1991,
47, 1215–1230.
[13] a) Z. Cao F. Gagosz, Angew. Chem. Int. Ed. 2013, 52, 9014–9018;
Angew. Chem. 2013, 125, 9184–9188; b) W. Rao, Sally, S. N. Berry, P.
W. H. Chan, Chem. Eur. J. 2014, 20, 13174–13180; c) Y.-W. Sun, X.-Y.
Tang, M. Shi, Chem. Commun. 2015, 51, 13937–13940; d) Y. Li, C.-Z.
Zhu, J. Zhang, Eur. J. Org. Chem. 2017, 6609–6613; e) J. Zhao, S. Yang,
X. Xie, X. Li, Y. Liu, J. Org. Chem. 2018, 83, 1287−1297; f) R. Ma, B. W.
Gung, Tetrahedron 2020, 76, 130840.
[23] E. L. Ghisalberti, Phytochemistry 1994, 37, 597–623.
[24] The gold(I)-catalyzed reaction of 1,3-dien-8-ynes with diazo esters sleads
to fused 1,4-cycloheptadienes by a formal (4+2+1) cycloaddition involving
a Cope rearrangement: Y.-J. Wang, X.-X. Li, Z. Chen, J. Org. Chem. 2020,
85, 7694−7703.
[14] a) M. A. Drew, S. Arndt, C. Richardson, M. Rudolph, A. S. Hashmi, C. J.
T. Hyland, Chem. Commun. 2019, 55, 13971–13974; b) J. Gonzꢀlez, A.
de la Fuente, M. J. Gonzꢀlez, L. Dꢁez de Tejada, L. A. Lꢂpez, R. Vicente,
Beilstein J. Org. Chem. 2019, 15, 285–290.
[25]
A
similar effect has been found in other gold(I) catalyzed
12 13
a, e]
transformations.[
[15] Dienediynes can undergo
a gold(I)-catalyzed cyclopropanation/Cope
[26] Reaction with catalyst D afforded in this case a complex mixture of 4d
together with other products.
rearrangement/C-H activation sequence to form polycyclic structures: a)
P.-J. Cai, Y. Wang, C.-H. Liu, Z.-X. Yu, Org. Lett. 2014, 16, 5898–5901;
b) Y. Wang, P.-J. Cai, and Z.-X. Yu, J. Am. Chem. Soc. 2020, 142, 2777-
2786.
[27] Propargyl acetates are known to undergo competing 1,2-migration under
13
]
gold(I) and gold(III) catalysis,[
which could explain the lower yield
compared to PNP.
[16] For a review, see: a) M. Mato, C. García-Morales, A. M. Echavarren,
ChemCatChem 2019, 11, 53–72; for selected examples of the generation
of vinyl carbenes by retro-Buchner reaction, see: b) C. R. Solorio-
Alvarado, Y. Wang, A. M. Echavarren, J. Am. Chem. Soc. 2011, 133,
11952–11955; c) B. Herlé, P. M. Holstein, A. M. Echavarren, ACS Catal.
2017, 7, 3668–3675; d) M. Mato, B. Herlé, A. M. Echavarren, Org. Lett.
2018, 20, 4341–4345; e) M. Mato, A. M. Echavarren, Angew. Chem. Int.
Ed. 2019, 58, 2088–2092; Angew. Chem. 2019, 131, 2110–2114; f) M.
Mato, I. Martín-Torres, B. Herlé, A. M. Echavarren, Org. Biomol. Chem.
2019, 17, 4216–4219.
[28] Y. Hashidoko, S. Tahara, J. Mizutani, Z. Naturforsch. 1992, 47c, 353–359.
[29] M. Mato, C. García-Morales, A. M. Echavarren, ACS Catal. 2020, 10,
3564–3570.
[30] An energetically-reasonable concerted cyclopropanation pathway was
also located, which is higher in energy (∆∆G‡ = 1.2 kcal/mol) than the
stepwise pathway. We have also studied the cis-trans rotation barrier
between the open intermediates, which allows for a reversible trans to cis
isomerization, explaining the experimental observation of obtaining 1,4-
cycloheptadiene 3a as only product. For details and full discussion, see
supporting information.
[17] For examples of gold(I)-catalyzed cyclization/migration sequences, see:
a) E. Jiménez-Núñez, M. Raducan, T. Lauterbach, K. Molawi, C. R.
Solorio, A. M. Echavarren, Angew. Chem. Int. Ed. 2009, 48, 6152–6155;
Angew. Chem. 2009, 121, 6268–6271; b) M. Gaydou, R. E. Miller, N.
Delpont, J. Ceccon, A. M. Echavarren, Angew. Chem. Int Ed. 2013, 52,
6396–6399; Angew. Chem. 2013, 125, 6524–6527; c) D. Leboeuf, M.
Gaydou, Y. Wang, A. M. Echavarren, Org. Chem. Front. 2014, 1, 759; d)
J. Carreras, M. Livendahl, P. R. McGonigal, A. M. Echavarren, Angew.
Chem. Int. Ed. 2014, 53, 4896–4899; Angew. Chem. 2014, 4996–4999.
[31] P. Calleja, Ó. Pablo, B. Ranieri, M. Gaydou, A. Pitaval, M. Moreno, M.
Raducan, A. M. Echavarren, Chem. Eur. J. 2016, 22, 13613–13618.
[32]
A slightly different energy profile was found for the reaction with
cyclohexadiene instead of cyclopentadiene, explaining the different
selectivity of the two substrates. See supporting information for details.
[33] See supporting information for control experiments.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012092
Angewandte Chemie International Edition
TOC
Metal vinyl carbenes generated by retro-Buchner reaction or an
enyne cycloisomerization cascade react with 1,3-dienes to afford
complex 1,4-cycloheptadienes in a formal (4+3) cycloaddition
process. A combination of experiments and computations provides
a
full mechanistic picture in which two pathways,
a
vinylcyclopropanation/Cope rearrangement or a non-concerted
(4+3) cycloaddition, can compete depending on the substitution
pattern of the substrate.
This article is protected by copyright. All rights reserved.